Institute of Chemistry, University of Silesia, Szkolna 9, 40-006 Katowice, Poland.
UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
Dalton Trans. 2019 Sep 14;48(34):13081-13093. doi: 10.1039/c9dt02894c. Epub 2019 Aug 14.
2,6-Bis(thiazol-2-yl)pyridines functionalized with 9-anthryl (L), 9-phenanthryl (L), and 1-pyrenyl (L) groups were used for the preparation of [Pt(L)Cl]CFSO (1-3). The constitution of the Pt(ii) complexes was determined by H and C NMR spectroscopy, HR-MS spectrometry, elemental analysis and X-ray analysis (for (1)). The electrochemical and photophysical properties of [Pt(L)Cl]CFSO were compared with the behaviour of the Pt(ii) complexes with aryl-substituted 2,2':6',2''-terpyridine ligands. What is noteworthy is that the coordination ability of dtpy toward the Pt(ii) centre was investigated for the first time. All complexes were tested in vitro by MTS assay on four tumor cell lines, A2780 (ovarian carcinoma), HTC116 (colon rectal carcinoma), MCF7 (breast adenocarcinoma), and PC3 (prostate carcinoma) and on normal primary fibroblasts. Compounds (1-3) showed a dose dependent antiproliferative effect in the A2780 cell line with (3) > (2) > (1) and this loss of A2780 cell viability was due to a combination of an apoptotic cell death mechanism via mitochondria and autophagic cell death. Exposure to IC concentration of (2) induced an increase in the number of apoptotic nuclei and a depolarization of the mitochondrial membrane which is consistent with the induction of apoptosis while exposure to IC concentration of (3) showed an increase in the apoptotic nuclei with a slight hyperpolarization of the mitochondrial membrane that might indicate an initial step of apoptosis induction. The complexes (2) and (3) induce an increase in the production of intracellular ROS which is associated with the trigger of the apoptotic pathways. The ROS production was augmented by the presence of oxidants and correlated with an increase of oxygen radicals. The IC of (2) and (3) (4.4 μM and 2.9 μM, respectively) was similar to the IC of cisplatin (3.4 μM) in the A2780 cell line, which together with their low cytotoxicity in normal fibroblasts, demonstrates their potential for further studies.
用 9-蒽基（L）、9-菲基（L）和 1-苝基（L）取代的 2,6-双（噻唑-2-基）吡啶被用于制备[Pt（L）Cl]CFSO（1-3）。Pt（ii）配合物的组成通过 H 和 C NMR 光谱、高分辨率质谱、元素分析和 X 射线分析确定（对于（1））。[Pt（L）Cl]CFSO 的电化学和光物理性质与具有芳基取代的 2,2':6',2''-三联吡啶配体的 Pt(ii)配合物的行为进行了比较。值得注意的是，首次研究了 dtpy 对 Pt(ii)中心的配位能力。所有配合物均通过 MTS 测定法在四种肿瘤细胞系（A2780（卵巢癌）、HTC116（结肠直肠癌）、MCF7（乳腺癌）和 PC3（前列腺癌））和正常原代成纤维细胞上进行了体外测试。化合物（1-3）在 A2780 细胞系中表现出剂量依赖性的增殖抑制作用，（3）＞（2）＞（1），并且 A2780 细胞活力的丧失是由于线粒体和自噬细胞死亡的凋亡细胞死亡机制的组合。暴露于 IC 浓度的（2）诱导凋亡核数量增加和线粒体膜去极化，这与诱导凋亡一致，而暴露于 IC 浓度的（3）显示凋亡核数量增加，线粒体膜轻微超极化，这可能表明凋亡诱导的初始步骤。配合物（2）和（3）诱导细胞内 ROS 产生增加，这与凋亡途径的触发有关。ROS 的产生增加了氧化剂的存在，并与氧自由基的增加相关。（2）和（3）的 IC（分别为 4.4 μM 和 2.9 μM）与 A2780 细胞系中顺铂的 IC（3.4 μM）相似，并且它们在正常成纤维细胞中的细胞毒性较低，表明它们具有进一步研究的潜力。
